A growing body of evidence has implicated dementia family caregiving as a risk factor for mental and physical health. Recent work provides evidence of one core pathway behind the diverse health risks associated with caregiving and other chronic stressors among older adults: sustained overproduction of a key proinflammatory cytokine, interleukin-6 (IL-6). This study will address whether genes for two proteins involved in serotonin (5-HT) signaling, the 5-HT transporter (5-HTT) and the 5-HT1A receptor, are susceptibility genes for depression and anxiety in 192 dementia spousal caregivers and 192 sociodemographically-matched noncaregiver controls. Use of a caregiver sample provides a way to replicate and extend key 5-HT vulnerability findings with a aging population that is clearly at risk;moreover, given the links between depression and enhanced secretion of IL-6 and tumor neurosis factor-alpha (TNF-a), we can also assess ties between genetic vulnerability to depression and overproduction of key proinflammatory cytokines. Additionally, this study will expand the well-documented associations between stress or depression and markers of inflammation by investigating the effects of depression, anxiety, and chronic stress on production of IL-6, CRP, and TNF-a, as well as the effect of genetic variation in these three markers on expression levels. Thus, we will also examine polymorphisms for IL-6, TNF-a, and CRP, and assess whether the differences in cytokine levels among the various groups (noncaregivers vs. caregivers, depression vs. no depression) are influenced by the cytokine genotypes, as well as relationships with age. Our specific aims are: 1) to determine if 5-HTT and the 5-HT1A receptor represent susceptibility genes for depression and anxiety among caregivers and noncaregiving controls;2) to determine the effects of polymorphisms in the genes for IL-6, CRP, and TNF-a on the relationship between cytokine expression levels and depression and anxiety in caregivers and noncaregiver controls;3) to determine the extent to which the chronic stresses of caregiving, depressive and anxiety symptoms, genetic vulnerability (polymorphisms for 5-HTT and 5-HT1A), and genetic variability (polymorphisms for IL-6, CRP, and TNF-a) influence proinflammatory responses following the occurrence of stressful life events;and 4) to determine the interactive contributions of age and distress to proinflammatory cytokine and CRP production. The proposed study will expand our knowledge of how genetic polymorphisms interact with environmental stressors to enhance risk for adverse mental and physical health changes.